Detection of Atherosclerotic Plaque Progression In Vivo using Magnetic Resonance Imaging and the Fibrin-Targeted Contrast Agent, EP-2104R

Sarah Forbes, Andrea Wiethoff, Marcus Makowski, Rene Botnar. King’s College London, London, United Kingdom.

Myocardial infarction is often the first manifestation of coronary heart disease and in the majority of cases is the result of plaque rupture and subsequent thrombosis. New imaging techniques that provide information on atherosclerotic plaque composition and biological processes associated with plaque progression and destabilization are required to improve the detection of “vulnerable” rupture prone plaques. Molecular magnetic resonance imaging (MRI) looks promising as a non-invasive modality for this purpose whilst fibrin represents a potential novel biomarker of plaque instability, having been detected in advancing, ruptured and eroded human lesions. This study aims to investigate the feasibility of molecular MRI of fibrin in the development and progression of plaques using a model of atherosclerosis and a fibrin targeted contrast agent, EP-2104R.

Contrast agent uptake was determined in the brachiocephalic arteries of twenty homozygous 71% C57BL/6, 29% 129 male ApoE -/- mice and eight C57BL/6 male age-matched WT control mice, all between 30-35g. ApoE -/- mice fed a high fat diet (HFD) for 4, 8 and 12 weeks and normal chow fed WT mice underwent molecular MRI pre- and 2 hours post i.v. administration of 10µmol/kg EP-2104R (EPIX Pharmaceuticals). MRI was performed using a pseudo cardiac-triggered inversion-recovery gradient-echo sequence with a spatial resolution of 0.1 x 0.1 x 0.5 at 3T (Achieva, Phillips). Within the vessel wall the contrast-to-noise (CNR) was determined using Osirix imaging software and compared to the gadolinium concentration detected by inductively coupled plasma mass spectrometry (ICP-MS) after removal of the artery.

EP-2104R significantly enhanced the visibility of plaques in 4, 8 and 12 week HFD mice compared to their non-contrast enhanced MR images (P< 0.05, unpaired Student’s t test), and compared to WT images (P< 0.001, one-way ANOVA and Dunnett’s test). During the HFD EP-2104R enhanced the plaque visibility and increased the gadolinium concentration in the vessel wall, with the 12 week HFD mice displaying the highest plaque CNR (P< 0.01, one-way ANOVA and Bonferroni’s test) and gadolinium concentration.

These results demonstrate a gradual increase in fibrin during atherosclerosis in vivo, thus potentially enabling the selective enhancement of advancing coronary plaques by EP-2104R and illustrating the potential of this agent as an imaging biomarker for detecting subclinical atherosclerosis